1. Field of the Invention
My invention relates to a vented microcradle for use in an incubator system specifically designed to maintain a premature infant in a controlled care environment from creation to implantation. The incubator system is thus an engineered environment specifically designed for the care of human embryos and hatchlings. The engineered environment is preferably a micro intensive care unit (μICU). My invention is intended for intimate combination with my teaching in U.S. Pat. No. 6,694,175 for a “Method of monitoring the body temperature of human embryos and hatchlings”, which historically is the first patent for pre-implantation patient care to be classified under incubators for premature infants (current U.S. class/subclass 600/22).
A human is an embryo only from conception to hatching. Hatching is an event that takes place when an embryo escapes the shell of the egg that he or she was conceived in. A human is a hatchling only from hatching until implantation (nidation).
A number of authorities still persist in using certain terms in an incorrect fashion, due in part to ignorance about the human hatching event. This circumstance requires one to be especially discerning in considering prior art uses of various terms (e.g., embryo).
A human embryo or hatchling is a prenid (“PRE-nid”), which means a prenidial (“pre-NID-e-al”) infant; thus, an infant is a prenid up to implantation. The term prenid is especially convenient because it encompasses both human embryos and hatchlings. The word prenid is derived by shortening of pre-nidation, which means pre-implantation, and the word prenidial is the adjectival form. To clarify this etymology, note that the nidus (“NID-us”), Latin for nest, refers to the uterine cavity; hence, prenidal (“pre-NIGH-dal”) means before the baby enters the uterine cavity, e.g., via the fallopian tube. In contrast, the nidia (from L. nidus, nest) is the settlement the baby makes at implantation (compare L. colonus, colonia), and so prenidial means before the baby implants, i.e., establishes a settlement in the nest.
Outside the maternal body, prenidial infants are premature infants because it is premature for them to be outside the maternal body on their own. Prenidial gestation refers to a maternal, bodily provision for prenidial development as well as to prenidial developmental needs in general, whereas prenidial incubation refers to an engineered provision for development outside the maternal body in a manner analogous to natural gestation. Thus, sophisticated incubator systems for premature infants prior to implantation are termed prenidial incubators. Prenidial incubators are like neonatal incubators, except their technology pertains to patient care before implantation. Hence, my invention relates to a vented microcradle for a prenidial incubator.
Technically speaking, “in vitro fertilization” refers only to the event or act of fertilization taking place in vitro, and not to subsequent care. In contrast, the whole practice of caring for the baby up to implantation, whether inside or outside the maternal body, is termed prenidial medicine, and care outside the maternal body is termed prenidial incubation. A prenidial incubator is required for care prior to transfer for children created by in vitro fertilization.
But even apart from in vitro fertilization, prenidial incubators find use whenever a baby needs to be taken from the maternal body and transferred to a prenidial incubator. For example, technology is under development that will eventually enable us to readily detect a prenid within the maternal body. U.S. Pat. No. 6,787,324 (Jordan et al.) for a “Method and apparatus for detecting conception in animals” is noted as an example of emerging veterinary and human medical research in this direction. Thus, if the mother dies in a traffic accident for example, then upon detection her baby can be transferred to a prenidial incubator for care while awaiting transfer to an adoptive mother. Similarly, if for example the mother's fallopian tube is blocked and the baby is trapped, or for example if the mother requires treatments that cannot be safely done with the baby present, the baby might need to be temporarily transferred to a prenidial incubator and then either transferred back or transferred to a surrogate mother.
Early neonatal incubators suffered from a lack of fresh air because a patient's need for proper ventilation was not originally understood. As Alan Brown and Ruggles George report in the Archives of Pediatrics in 1917, “Absence of fresh air was a disadvantage in an enclosed incubator that even properly regulated heat did not outweigh.” In a practical approach to the problem, Edwin B. Cragin reports in 1914 in the Journal of the American Medical Association on the use of “a small electric fan” in the Sloane Hospital incubator to maintain “a gentle current of filtered air passing through” the incubator. The technology of the vented microcradle is analogous in principle to that of a modern, ventilated neonatal enclosure, except that prenidial infants live in a fluid incubation medium whereas neonatal infants live in the air we breathe. Thus, when speaking of ventilation for a prenidial infant, one means a gentle flowing of the fluid incubation medium over the infant's egg (embryo stage) or body (hatchling stage) so as to refresh needed substances and remove wastes. Accordingly, fluidic ventilation is not to be confused with an air system for an incubator; but note however that in a prenidial incubator the air system may contribute to fluidic ventilation by way of influencing the chemical balance (O2, CO2, etc.) of the fluid incubation medium, e.g., the CO2 content can influence pH.
2. Prior Art
During prenidial gestation infants live in a fluid medium, and then from implantation until birth infants live attached to the maternal body. Because prenidial infants live in a fluid medium and are of microscopic size, caring for them outside the maternal body involves different technologies than caring for premature infants in later development. Notably, prenidial incubation is now a rapidly evolving technology, inspired mainly by advances in integrated microfabrication technology (IMT). To make a comparison to the history of progress in the care of premature infants in neonatal development, early efforts of neonatal incubation faltered for failure to thermoregulate and ventilate the babies in a competent fashion. Sadly, the incubator care of premature infants in prenidial development faltered for the same reasons.
Fortunately, the modern art of prenidial incubation has been introduced by my teaching on the competent manner of thermoregulation in U.S. Pat. No. 6,694,175 for a “Method of monitoring the body temperature of human embryos and hatchlings” (incorporated here by way of reference). Prior to my teaching, practitioners of what was called in vitro fertilization failed to grasp the correct principles of thermoregulation, and so their crude, petri dish based incubator systems did not function competently; in a nutshell, they confused the temperature of the fluid incubation medium, in which prenidial infants are kept, with the infant's endogenous actual body temperature. In other words, they confused the temperature of the infant's environment with a measure of the infant's own body temperature. This problem of incompetent thermoregulation led to enormous infant mortality rates, particularly among infants being incubated in the later stages of prenidial development since these stages reflect increased endogenous heat production on the part of the infant. (Californiaa, E. Thermoregulation of human embryos and hatchlings in a prenidial incubator using infrared microthermography. Trends in Reproductive Biology. 2005;1:63–67.)
Of historical interest, pediatric historian Thomas E. Cone, Jr. notes that similar incompetence persisted during the early development of neonatal incubators, and, moreover, that it was an understanding and solution of this problem that prompted the modern age of neonatal care. (Cone, T. E., Jr. History of the Care and Feeding of the Premature Infant. Boston: Little, Brown, 1985. p. 21–22.) But rather than realizing their own incompetence, practitioners of in vitro fertilization simply attributed their shortcomings to “genetic causes” as opposed to environmental causes, even despite it being fairly well known that improper thermoregulation at this stage can induce a wide spectrum of gross chromosomal abnormalities, also known as cytogenetic abnormalities (e.g., aneuploidies).
My method in U.S. Pat. No. 6,694,175 solves the problem of incompetent thermoregulation. According to this method, the techniques of infrared microthermography are used to distinguish a baby's temperature from the temperature of the surrounding environment, and a feedback loop is used to maintain optimal temperature for the baby for the sake of proper thermoregulation. (Californiaa, E. Ibid.)
As stated above, in developing modern neonatal incubators, along with the most essential step of thermoregulation, another key step proved to be ventilation. By analogy, the need for similar progress in ventilation technology in the context of prenidial incubation forms the necessity of my present invention. Because neonates live in the air we breathe, neonatal ventilation is gas/vapor phase ventilation. In contrast, because prenids live in the fluid of the uterine tube and uterine cavity, prenidial ventilation is liquid phase ventilation.
Neonatal incubation differs from prenidial incubation in that neonates require ventilation for oxygen and humidity and to expel carbon dioxide whereas prenids also require ventilation for nourishment and other waste removal. In other words, neonates breathe air, are fed internally, and their diapers are changed, whereas prenids transfer all metabolic resources and wastes via the fluid medium in which they live submerged.
Hunter (U.S. Pat. No. 4,574,000—“Artificial fallopian tube”) is a clear forerunner in appreciating the need for a human embryo or hatchling to experience fluidic ventilation in a fabricated device. He speaks of using a micropump to infuse a nutrient solution through an artificial (fallopian) tube to ensure that a fertilized “egg is provided with an adequate supply of fresh nutrient solution”. (column 5, lines 38–50). The teaching of Thompson et al. in U.S. Pat. No. 6,673,008 for a “Fallopian tube and method of in vitro fertilization and embryo development” also appreciates the necessity of fluidic ventilation for prenidial development in likeness to the fluidic ventilation provided by the fallopian tube. In effect, Thompson et al. roughly mimic Hunter's approach with an externalized (as opposed to a prosthetic) device. But unlike Hunter's device, theirs is not a microfluidic device. As shown in FIG. 1, Thompson et al. rely on a well-type structure 1 with a microporous floor 2 to keep an embryo P (“P” for prenid) housed at the bottom of an enclosed tank 3. Campbell et al. in published application US 2002/0068358 also teach a well for housing an embryo. The teaching of Beebe et al. in U.S. Pat. No. 6,193,647 for a “Microfluidic embryo and/or oocyte handling device and method” somewhat appreciates the necessity of fluidic ventilation, however, their appreciation appears to be compromised by their objective of employing fluid flow to roll the eggs of embryos; consequently, the rate of fluid flow they suggest appears to be much too harsh. For given that (per Thompson et al.) the average velocity of an embryo along the length of the fallopian tube is roughly on the order of 0.2 micrometers per second, with fastest transit rates roughly on the order of 0.35 micrometers per second in portions of the fallopian tube, the fluid flow rates suggested by Beebe et al., with embryos traveling at a velocity of 187 to 250 micrometers per second for a fluid flow rate of 380 micrometers per second, appear to be excessive by several orders of magnitude. As shown in FIG. 2, Beebe et al. teach a channel-type structure for housing an embryo P. Beebe et al. also teach a well-type structure for housing an embryo.
IMT (integrated microfabrication technology) employs diverse arts to make small size systems and devices. IMT technology includes submillimeter, micrometer, and nanometer technologies, and often incorporates these with larger scale technologies. IMT designs offer important benefits such as intimate integration with electronic circuitry and the ability to manufacture arrays of designs on a single substrate. IMT arts especially relevant to this disclosure include micro electro mechanical systems (MEMS) technology and microfluidic technology. Note that microfluidic technology relates to fluid flow on a small scale and also includes micropump and microvalve technology.
A microcradle is a cradle engineered for a baby's “micro” size in early life. The micro size of prenidial infants makes them particularly amenable to microfabricated (IMT) systems and devices. Human eggs are spherical in shape. Eggs obtained from stimulated ovarian cycles will need to be matured if they are not quite ready for fertilization. Using unfertilized eggs obtained from stimulated ovarian cycles and matured in vitro under specific conditions before being fertilized, Roux et al. reported the morphometric (body size) parameters of human embryos in earliest development after being created by in vitro fertilization as being 157.4 microns for the outer diameter of the egg, 17.9 microns for the thickness of the shell, and 121.8 microns for the inner diameter of the egg which bounds the cells of the infant's body inside. However, these parameters can vary somewhat based on physical differences, maternal condition (e.g., increased age or smoking exposure has been associated with increased shell thickness), and the way unfertilized eggs arrive at maturity (i.e., naturally versus artificially) before fertilization. Note that at fertilization eggshells 10–20 microns thick with 120–140 micron outer diameters (100 micron inner diameters) are commonly reported. 100 microns is one-tenth of a millimeter. Composed of a protein matrix, not cells, the eggshell is often referred to as the zona pellucida (Latin for “clear zone”) because it is translucent under the microscope. The embryo will expand inside the egg near hatching time and the shell will become thinner. The baby uses specialized shell-breaker cells to make a hole in the shell and then squeezes through. The baby leaves an empty shell behind after hatching. By the time a hatchling is ready to implant, the entire body of the infant may measure as much as half a millimeter in total diameter. Hatchlings require special care because they can invade or breach structures and become attached, lodged, or lost; also, their body tissues are directly exposed. Thus, systems and devices engineered for prenidial infants must take into account various morphological, physiological, and behavioral parameters and tolerances.
Cecchi et al. (U.S. Pat. No. 6,448,069) teach a picket fence structure comprising posts to keep babies separated from one another in a communal setting while in their eggs. Their particular picket fence structure is characterized with hindsight in view of the present teaching as a type of microcradle in array form. They teach the advantage that communal life provides a mutual contribution of beneficial endogenous substances, and that the picket fence structure keeps the babies separated for track-keeping purposes. See FIGS. 3A–C. But even though their picket fence structure is in effect a type of a microcradle in array form, it is not characterized as a vented microcradle because they do not incorporate a ventilation system with their structure for the purpose of fluidic ventilation.
In discussion with me, Kim et al. have suggested adaptation of their microcage structure to form a microcradle in the context of μICU objectives. The microcage is fabricated using an IMT technology called surface micromachining. Referring to FIGS. 4A B, the microcage has the appearance of a sea anemone and opens and closes under the action of pneumatic pressure applied to a diaphragm under the cage. However, further development is needed to reduce the size of the microcage so that it can cradle a baby at conception.
Sadly, unimaginative reliance on crude petri dish practices has persisted in the field of in vitro fertilization; according to such practices, prenidial infants are left at the bottom of an ordinary petri dish without any type of cradle or support whatsoever, without any fluidic ventilation, and without a proper understanding of thermoregulation; the children are treated like lab specimens rather than as patients. Such practices are incompetent and in my experience those responsible have no wish to change.
In an effort to advance diplomatic regard for the rights of prenids as patients in medicine, my institution, Juridic Embassy, has sponsored new progress in fertility care. As a consequence of my research in this area, I initiated the Micro ICU Project in response to the general lack of care being provided to children created by in vitro fertilization. The synergy of the project was created by the needs of the children in light of impressive new engineering technologies, particularly MEMS. Using IMT technologies such as MEMS, complementary metal oxide semiconductor technology (CMOS), and microfluidics, as well as various large-scale technologies, the goal of the project is to perfect an elaborately engineered patient care environment for children in prenidial incubators. An engineered provision of this sophistication for human embryos and hatchlings is called a micro intensive care unit (micro ICU, μICU, μ-ICU).
One objective of the Micro ICU Project is to provide a means to cradle and ventilate a prenidial infant. This objective provides the subject matter of my present invention.
3. Statement of the Necessity
For a neonatal incubator, the cradle portion of the incubator must allow for easy access to a patient while at the same time affording proper thermoregulation and ventilation at all times. A well-designed prenidial incubator should offer the same advantages.
What is needed is a vented microcradle for a prenidial incubator.